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Characterization of the gut microbiota and identification of colitogenic bacterial species in core 1 O-glycans deficient mice
Mucus is one important component of the intestinal mucosal barrier, and loss of its functionality is associated with colitis in humans and mice. Mice deficient in core 1 O–glycans (TM–IEC C1galt1-/-) display a thinner mucus layer upon mutation of the glycosyltransferase enzyme (C1GALT1) responsible for core 1 O–glycans attachment, thus constituting an experimental model for human Ulcerative Colitis (UC). Under conventional conditions, these mice experience spontaneous inflammation of the colon. However, the exact role of the microbiota in colitis development in these mice has not been systematically investigated. Aimed to gain insights into the role of the microbiota in colitis when there is a breach in the mucus barrier, we characterized the gut microbiota of conventional TM–IEC C1galt1-/- mice, tested the requirement of bacteria for initiation of colitis, and identified bacterial species associated with disease in this mice model. Analysis of fecal bacterial populations by pyrosequencing of 16S rRNA tags showed that disease in conventional TM–IEC C1galt1-/- was associated with microbial dysbiosis manifested by increases in Lactobacillus and Clostridium species, and decreases in unclassified Ruminococcus and unclassified Lachnospiraceae . Under germ–free (GF) conditions, deletion of the C1GALT1 enzyme caused decreased goblet cells, but did not result in inflammation, showing that bacteria are required for disease development. Monoassociation of GF TM–IEC C1galt1-/- revealed that the selected bacterial species differ significantly in the ability to induce disease. Bacteroides thetaiotaomicron and Bacteroides vulgatus showed association with induction of inflammation in this mice model. Bacteroides sartorii , Clostridium symbiosum , Akkermansia muciniphila , and Lactobacillus johnsonii not only did not cause manifestations of disease, but they induced high levels of secretory–IgA. Findings suggest that the relationship between the commensal microbiota and the intestinal epithelium skews towards development of inflammation in the presence of a defective mucus layer, but not all dysbiotic shifts contribute to disease. Bacteroides species, which were not enriched in conventional TM–IEC C1galt1-/- mice, caused inflammation, while Lactobacillus johnsonii (enriched during colitis) did not. This thesis represents the first reported evidence of microbial dysbiosis caused by lack of core 1 O–glycans, and forms the basis for future work aimed to indentify bacterial factors related to disease.
Perez-Munoz, Maria Elisa, "Characterization of the gut microbiota and identification of colitogenic bacterial species in core 1 O-glycans deficient mice" (2013). ETD collection for University of Nebraska - Lincoln. AAI3589771.